Bacterial respiratory infections are a major health problem in the United States, and especially amongst patients with compromised immunological defense mechanisms. Patients with Cystic Fibrosis (CF), Acquired Immune Deficiency Syndrome (AIDS), congestive heart failure, chronic lung disease, cancer, and the elderly population all possess an increased risk of respiratory infection. For example, the debilitation of the lungs in CF patients is associated with accumulation of purulent sputum produced as a result of chronic endobronchial infections caused by opportunistic infectious organisms. Nearly all individuals suffering from CF eventually die of respiratory failure.
P. aeruginosa is a small, aerobic gram-negative rod that inhabits soil, water, plants, and animals, including humans. Although P. aeruginosa occasionally colonizes the skin, external ear, upper respiratory tract or large bowel of healthy humans, these infections are usually mild. Infection by P. aeruginosa can be much more serious in immunocompromised individuals, causing a number of complications including: chronic infections of the lower respiratory tract of CF patients; bacteremic pneumonia, which complicates hematopoetic malignancies following chemotherapy-induced severe neutropenia; and primary pneumonia in patients with AIDS, congestive heart failure, and chronic lung disease.
S. aureus is a staphylococcal bacteria that is a major health problem due to its tenacity, potential destructiveness, and increasing resistance to antimicrobial agents. Pneumonia arising from S. aureus infection most commonly follows tracheal intubation during hospitalization or is secondary to a viral respiratory infection. Such infections are very common in patients who are elderly and/or institutionalized. In addition, respiratory infection of S. aureus may cause septic pulmonary embolization in settings such as right-sided endocarditis, which is common in intravenous drug users, and septic thrombophlebitis, which is oftentimes a complication of an indwelling venous catheter. S. aureus is also a health problem in immunocompromised patients, as it is often difficult to treat with conventional systemic antibiotics.
Current treatments for these and other pulmonary bacterial infections are often expensive, non-specific, and must use very large doses in order to be effective. In one example, the present treatment of choice for chronic bronchitis or bronchiectasis seen in CF patients is parenteral administration of an aminoglycoside and a beta-lactam active against P. aeruginosa. However, aminoglycoside penetration into the bronchial secretions is poor at approximately only about 12% of the peak serum concentration (Rev. Infect. Dis., 3:67 (1981)). According to Advances in Pediafric Infectious Diseases, 8:53 (1993), sputum itself is inhibitory to the bioactivity of aminoglycosides because of its high ionic strength and the presence of divalent cations. This inhibitory activity can be overcome by increasing the concentration of aminoglycosides in the sputum to ten times the minimum inhibitory concentration of the particular P. aeruginosa isolate (J Infect. Dis., 148:1069 (1983)), but this increases the risk of systemic toxicity including ototoxicity and nephrotoxicity. Intravenous therapy may increase hardship on the patient, and frequently requires hospitalization, which increases treatment costs and exposes the patient to other potential infections.
One of the first studies using aerosolized antibiotics for the treatment of CF was reported in Lancet, 22:1377-9 (1981). A controlled, double-blind study on twenty CF patients demonstrated that aerosol administration of carbenicillin and gentamicin can improve the health of CF patients. Unfortunately, the physical properties of many antibiotics, such as aminoglycosides require a relatively high dose of the drug for aerosolization and such treatment then becomes rather expensive.
There is a need in the art for a cost-effective and therapeutically efficacious treatment for bacterial respiratory infections, and especially for respiratory infections in immuno-compromised patients. There is also a need for an efficient method for specifically introducing antibiotic agents to the respiratory tract to the site of the infection.